Emerging Roles of Human Prostatic Acid Phosphatase

Review Biomol Ther 21(1), 10-20 (2013)

Hoon Young Kong and Jonghoe Byun*

Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin 448-701, Republic of Korea

Abstract Prostate cancer is one of the most prevalent non-skin related cancers. It is the second leading cause of cancer deaths among males in most Western countries. If prostate cancer is diagnosed in its early stages, there is a higher probability that it will be completely cured. Prostatic acid phosphatase (PAP) is a non-specific phosphomonoesterase synthesized in prostate epithelial cells and its level proportionally increases with prostate cancer progression. PAP was the biochemical diagnostic mainstay for prostate cancer until the introduction of prostate-specific antigen (PSA) which improved the detection of early-stage prostate cancer and largely displaced PAP. Recently, however, there is a renewed interest in PAP because of its usefulness in prognosticating intermediate to high-risk prostate cancers and its success in the immunotherapy of prostate cancer. Although PAP is believed to be a key regulator of prostate cell growth, its exact role in normal prostate as well as detailed molecular mechanism of PAP regulation is still unclear. Here, many different aspects of PAP in prostate cancer are revisited and its emerging roles in other environment are discussed.

Key Words: Prostatic acid phosphatase (PAP), Prostate cancer, Biomarker, Prognosis, Diagnosis, Immunotherapy

INTRODUCTION correlates with prostate cancer progression in prostate cancer patients and that PAP could serve as a biochemical indicator Prostate cancer is one of the most prevalent non-skin for cancer treatment (Veeramani et al., 2005). Subsequently, cancers in men. In America, prostate cancer related death is serum PAP was widely studied as a surrogate marker for pros- ranked second out of all cancer related deaths in men, but its tate cancer until the establishment of prostate-specific anti- etiology has not been clearly identified yet (Hsing and Chok- gen (PSA) as the new standard (Veeramani et al., 2005). The kalingam, 2006). However, in contrast to many other cancers introduction of total PSA testing in blood has revolutionized that are difficult to treat, prostate cancer can be completely the detection and management of patients with prostate can- cured if it is detected in its early stage. Many prostate cancer cer. Indeed, PSA has been regarded as a strong prognostic markers including prostate-specific antigen (PSA), prostate marker for long-term risk of prostate cancer. The patients who specific membrane antigen (PSMA), prostate acid phospha- will eventually develop prostate cancer have increased total tase (PAP), and prostate stem cell antigen (PSCA) have been PSA levels years or decades before the cancer is diagnosed. identified so far (Truonget al., 1993; Hobisch et al., 1998; Bus- However, there is a growing need for novel biomarkers that semakers et al., 1999, Gupta et al., 2009; Madu and Lu, 2010; could aid in clinical decision making about biopsy and initial Batta et al., 2012), which all together can help to increase the treatment. This is due to the inherent biological variability of chance of earlier detection of prostate cancer (Table 1). total PSA levels which inevitably affects the interpretation of In 1938, which is 85 years after first identification of prostate clinical data. For example, total PSA velocity improves the cancer (Fig. 1), it was discovered that the activity of prostatic predictiveness of total PSA only marginally, limiting its value acid phosphatase (PAP) was increased in the circulation of the for prostate cancer screening and prognostication (Shariat et patients with prostate cancer (Gutman and Gutman, 1938). al., 2011). In this regard, it is encouraging that Swedish group This elevated PAP activity was especially higher in those pa- recently developed a novel miRNA index quote (miQ = [miR- tients with bone metastasis (Small et al., 2006; Sheridan et 96-5p×miR-183-5p]/[miR-145-5p×miR221-5p]) as an early al., 2007). Later on, it was established that blood PAP activity marker for prostate cancer with aggressive progression char-

Open Access http://dx.doi.org/10.4062/biomolther.2012.095 Received Dec 4, 2012 Revised Jan 10, 2013 Accepted Jan 14, 2013 This is an Open Access article distributed under the terms of the Creative Com- *Corresponding Author mons Attribution Non-Commercial License (http://creativecommons.org/licens- E-mail: [email protected] es/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, Tel: +82-31-8005-3194, Fax: +82-31-8021-7201 and reproduction in any medium, provided the original work is properly cited.

10 Kong and Byun. Varied Roles of Prostatic Acid Phosphatase

Table 1. Biomarkers of prostate cancer. Different classes of prostate cancer biomarkers are shown. The list is not exhaustive. The markers are mostly proteins in blood. DNA, RNA, and metabolite are also shown Biomarker Composition Change Purpose Reference Prostatic acid phosphatase (PAP) Protein Increase Diagnosis/ Taskén et al., 2005; Prognosis Veeramani et al., 2005; Makarov et al., 2009 Prostate-specific antigen (PSA) Protein Increase Diagnosis Li and Beling, 1973; Ercole et al., 1987; Stamey et al., 1987 Biomarker candidate a-Methylacyl coenzyme A racemase Protein Increase Diagnosis Rogers et al., 2004 (AMACR) B7-H3 Protein Increase Diagnosis/ Roth et al., 2007 Prognosis Caveolin-1 (Cav-1) Protein Decrease Prognosis Thompson et al., 2010 Chromogranin A (CGA, GRN-A) Protein Increase Prognosis Deftos, 1998 DAB2 interacting protein (DAB2IP) Protein Decrease Diagnosis Chen et al., 2002 Endoglin (CD 105) Protein Increase Prognosis Wikström et al., 2002 Early prostate cancer antigen (EPCA) Protein Increase Diagnosis Getzenberg et al., 1991 Goligiphosphoprotein 2 (GOLPH2) Protein Increase Diagnosis Kristiansen et al., 2008 Glutathione S-transferase P1 gene DNA Hypermethylation Diagnosis Lee et al., 1994 (GSTP1) (decrease) Human kallikrein 2 (hK2) Protein Increase Diagnosis Becker et al., 2000 Interleukin-6 (IL-6) Protein Increase Prognosis Hobisch et al., 1998 Ki-67 Protein Increase Diagnosis Gerdes et al., 1984; P504S/p63 Protein Increase Diagnosis Harvey et al., 2010 Prolactin-inducible protein Protein Increase Diagnosis Tian et al., 2004 (PIP/GCTFP15) Prostate cancer antigen-1 (PCA-1) Protein Increase Diagnosis Liu et al., 2007 Prostate cancer antigen 3 (PCA3 or DD3) RNA Increase Diagnosis Bussemakers et al., 1999 PDLIM4 gene (PDLIM4) DNA Hypermethylation Diagnosis Vanaja et al., 2006 (decrease) Prostate stem cell antigen (PSCA) Protein Increase Prognosis Reiter et al., 1998 Prostate-specific membrane antigen Protein Increase Diagnosis Brawer et al., 1992 (PSMA) Sarcosine Metabolite Increase Diagnosis Sreekumar et al., 2009 (Chemical) (in urine) STAMP1 Protein Increase Diagnosis Korkmaz et al., 2002 STAMP2 Protein Increase Diagnosis Korkmaz et al., 2005 STEAP Protein Increase Diagnosis Hubert et al., 1999 Transforming growth factor-b1 (TGF-b1) Protein Increase Prognosis Truong et al., 1993 Urokinase plasminogen activation (uPA) Protein Increase Diagnosis/ Gupta et al., 2009 Prognosis

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Fig. 1. History of PAP development. Illustrated timelines for prostate cancer and its biomarkers. The major breakthroughs and advances in prostate cancer research are shown. The rise, fall, and revival of PAP along with its emerging diverse roles are also depicted.

acteristics (Larne et al., 2012). They measured the expres- prostate cancer marker and studied widely in the past few de- sion of microRNAs (miRNA) using qRT-PCR in FFPE pros- cades, its physiological role is not clearly understood yet. As tatic tissue samples from a Swedish cohort of 49 patients with the name suggests, PAP shows phosphatase activity in acidic prostate cancer and 25 without cancer and found eight of 14 condition (pH 4-6) (Zelivianski et al., 1998). PAP enzymatic preselected miRNAs to discriminate between the two groups. activity occurs when PAP forms a homodimer that consists of Subsequently four discriminatory miRNAs were combined to two catalytically inactive subunits (50 kDa) bound by non-co- a quota. The miQ was found to successfully predict diagnosis valent bonds (Kuciel et al., 1990; Lee et al., 1991). Each sub- (p<0.0001) with high accuracy (AUC=0.931), significantly out- unit comprises two domains. The larger domain is an a/b type performing PSA. On the other hand, novel blood-based bio- composed of a central seven-stranded mixed b-sheet with a- markers including human glandular kallikrein 2 (hK2, Becker helices on both sides, while the smaller a-domain contains six et al., 2000), urokinase plasminogen activator (uPA) and its re- a-helices and is formed mostly by long-chain excursions from ceptor (uPAR, Gupta et al., 2009), transforming growth factor- the first domain (Ortlundet al., 2003; Hassan et al., 2010). The beta 1 (TGF-b1, Truong et al., 1993), interleukin-6 (IL-6) and inter-subunit hydrogen bonds observed are the side chain of its receptor (IL-6R, Hobisch et al., 1998) were identified and Gln 33 to main chain His 67 interactions, side chain of Gln 40 they also are expected to supplement or replace PSA for bet- to main chain of Val 97, and side chain of His 112 to side chain ter diagnosis, staging, prognostication, and monitoring (Kraus of Asp 76 (Jakob et al., 2000). et al., 2010). Recently, PCA3 (Bussemakers et al., 1999), and After cleavage of the 32 amino acids that make up PAP’s T2:ERG (Young et al., 2012) was suggested to be a novel signal peptide, PAP becomes approximately 41 kDa which is biomarker for prostate cancer. PCA3 is a noncoding RNA that its mature form (Roiko et al., 1990; Zelivianski et al., 1998). is found at high levels in prostate cancer compared to non- The PAP monomer has 6 conserved cysteine residues that cancerous prostate cells. T2:ERG is a fusion of the TMPRSS2 form 3 disulfide bonds (Cys129-Cys340, Cys183-Cys281 and gene that is regulated by androgens and ERG oncogene. Cys315-Cys319) together with three putative N-linked glyco- Found in 50% of prostate cancers, this fusion gene is hypoth- sylation sites (Van Etten et al., 1991). A high mannose-type esized to have a role in the development of prostate cancer carbohydrate binds to Asn61 and Asn301, while Asn188 resi- (Young et al., 2012). due partially sialylates (Jakob et al., 2000). Interestingly, these In this review, however, we will focus on PAP molecule be- glycosylation sites and active sites are conserved in all mam- cause an increasing number of studies have identified PAP as malian PAPs (Ostanin et al., 1994). The structure and active a significant prognostic factor for patients with intermediate- to site of PAP has been extensively characterized from various high-risk prostate cancer (Taira et al., 2007) and it is recently species (Hassan et al., 2010). Multiple sequence analyses used as a therapeutic target for immunotherapy (Drake, 2012; of human PAP with that of other mammalian PAPs revealed Sims, 2012). In addition, novel non-canonical functions of PAP close resemblance among one another. Interestingly, the hu- such as pain suppression and involvement in viral infection man PAP showed approximately 99% sequence homology will be discussed. with the panther, 94% with the monkey, 81% with the cow, 83% with the mouse and 80% with the rat. The major action of PAP is to dephosphorylate macromol- HUMAN PAP ecules with the help of catalytic residues (His12 and Asp258) that are located in the cleft between two domains (Hassan et Human PAP, also known as Acpp or prostatic specific acid al., 2010). Site-directed mutagenesis of amino acid residues phosphatase (PSAP), is a secreted glycoprotein (100 kDa) of PAP revealed that His12 and Asp 258 are critical residues enzyme (E.C. 3.1.3.2) that is synthesized in the prostate for enzymatic activity of PAP because H12D and/or D258A gland’s epithelial cells (Vihko et al., 1978). Although used as a mutant could not decrease phosphorylation level of ErbB- http://dx.doi.org/10.4062/biomolther.2012.095 12 Kong and Byun. Varied Roles of Prostatic Acid Phosphatase

Fig. 2. Binding sites and their corresponding factors which regulate human PAP expression. Trans-acting factors involved in the regulation of PAP are schematically represented together with their binding sites. NF-κB binds to AGGTGT motif at the -1254/-1249 region, which acts as a cis-acting element. This leads to tissue-specific upregulation of PAP expression through TNF-a or IL-1. Transcription factors enhance PAP transcription through the GAAATATGATA motif. −588/−585, −267/−237, +211/+241 and +1136/+1164 regions are associated with not tissue-specific upregulation of PAP, whereas −160/−130 and +239/+269 regions are associated with prostate tissue-specific upregulation. Androgen (A) - androgen receptor (AR) complex binds to androgen response element (ARE) for positive and/or negative regulation of PAP transcription. ARE located in −151/140 region is involved in enhancing PAP transcription, whereas, +218/+229 and +244/+255 regions are associated with transcriptional inhibition of PAP. A: androgen; AR: androgen receptor; NGF: nerve growth factor; EGF: epidermal growth factor; TPA: tissue plasminogen activator; IL: interleukin; TGF-b: Transforming growth factor-b; NF-kB: nuclear factor kappa B; TNF-a: tumor necrosis factor-a.

2 (Zhang et al., 2001). Histidine (H257) and arginine (R11, increased amounts in men who have prostate cancer. Indeed, R15, R54, R79) residues are also important for PAP activity robust expression of PAP was detected in high Gleason score (Ostanin et al., 1994). The dephosphroylation mechanism of prostate cancer (Gunia et al., 2009). But PAP expression is PAP is similar to that of fructose-2,6-bisphosphatase (Okar et also enriched in normal prostate cells as well as in prostate al., 2000). The His12 acts as a nucleophile and conjugates cancer tissue as determined by real-time qPCR (Graddis et with the substrate to form a phosphohistidine intermediate. al., 2011). When compared with other tissue, PAP mRNA level Then, for recycling of the enzyme and dephosphorylation, is 50-5,000 fold higher in normal prostate tissue, and 110- Asp258 hydrolyzes phosphohistidine (Ostanin et al., 1994; 6,000 fold higher in prostate cancer tissue. PAP can also be Sharma and Juffer, 2009). Although the dephosphorylation detected in various tissues other than prostate such as brain, mechanisms and catalytic active site of PAP are well-known, kidney, liver, lung, placenta, salivary gland, spleen, thyroid and there are very few substrates that have been identified so far. thymus cells (Solin et al., 1990). PAP is absent in breast carci- The few that have been identified include AMP, phosphoty- noma tissue in contrast to normal breast tissue where PAP can rosine, phosphocholine, phosphocreatine and ErbB-2 (Dave be detected (Wang et al., 2005). More recently, however, PAP and Rindani, 1988). Because PAP has the potential to act as was discovered in large quantities in breast cyst fluid (BCF), the protein tyrosine phosphatase, there could be many other especially in metaplastic epithelium (intracystic Na/Klessthan, substrates that have yet to be identified. Identification of such 3 type I), suggesting the role of PAP in protecting several car- substrates would help to delineate the signal transduction cinomas by activating TGF-b as a similar molecule to PSA pathways of PAP, which can contribute to better diagnosis, (Erbas et al., 2007). Further study is needed to elucidate the treatment and prevention of prostate cancer. role of PAP on TGF-b activation. In colon carcinoma, PAP was detected in only 40% of samples at a lower level than normal prostate or prostate carcinoma (Wang et al., 2005). The acid TISSUE EXPRESSION OF PAP phosphatase that is expressed in placenta and liver is mostly located in lysosome, and are therefore termed lysosomal acid In human, PAP is one of the major proteins secreted by phosphatase (LAP) (Shan et al., 2003). prostate columnar epithelium secretory cells following puberty (Graddis et al., 2011). PAP protein has been determined to be about 0.5 mg/g wet weight of prostate tissue (Goldfarb et REGULATION OF PAP GENE EXPRESSION al., 1986) and approximately 1 mg/ml in seminal fluid (Ron- nberg et al., 1981). PAP expression is associated with the sex The PAP gene is located in chromosome 3q21-23 in hu- hormone testosterone which determines secondary sexual mans (Winqvist et al., 1989). Alternative splicing generates characteristics (Goldfarb et al., 1986). PAP may be found in two types of PAP transcripts; transmembrane PAP which

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consists of 11 exons (exon 1-9, 10a and 11), and cellular and with this, prolonged passage of LNCaP cells led to a decrease secretory PAPs having 10 exons (exon 1-9 and 10b) (Zelivi- in the cPAP level, which corresponds to the loss of their andro- anski et al., 1998; Veeramani et al., 2005; Kong et al., 2011). gen sensitivity and an increase in the growth rate and tumori- The length of 3’-UTR of transmembrane PAP is shorter than genicity. Conversely, ectopic expression of cPAP in AR-posi- those of cellular and secretory PAPs: 405 bp versus 874 bp tive, PAP-null cells could restore their androgen sensitivity and (Kong et al., 2011). The molecular mechanisms underlying a decrease in their growth rate and tumorigenicity (Lin et al., PAP gene regulation are not fully understood. However, many 1998; Meng et al., 2000; Lin et al., 2001). Moreover, the level trans-acting factors including androgen/androgen receptor, of cPAP inversely correlated with prostate cancer progression NF-κB, TNF-a and IL-1 are involved in the regulation of PAP despite an elevated level of blood sPAP (Abrahamsson et al., gene expression (Fig. 2). In human prostatic carcinoma, two 1988). In another aspect, PAP proteins isolated from prostate major transcription initiation sites exist, one at 56bp and the cancer patients had lower pI values and longer half-lives than other 91bp upstream of ATG codon (Zelivianski et al., 1998). normal tissues (Veeramani et al., 2005). Lin et al. could show The androgen and androgen receptor (AR) complex seems that the decreased clearance rate of this cancerous PAP in to be essential for prostate development and function. In PAP animal model can be explained by altered post-translational regulatory regions, an androgen response element (ARE) ex- modification such as increased sialyation (lower pI). Based ists in 3 sites (−151/−140, +218/+229, +244/+255) which are on these findings, it was suggested that the elevated blood androgen-AR complex binding motifs. When androgen levels PAP in prostate cancer patients is due to combined effects of are normal, the −151/−140 site is involved in enhancing PAP increased tumor mass and increased half-life of sPAP (Veera- transcription level. However, when androgen level is low, the mani et al., 2005). On the other hand, recent studies revealed +218/+229 and +244/+255 sites act as negative regulators that the splice variant (TM-PAP) was expressed in nonprostat- of PAP transcription (Porvari et al., 1995; Kong et al., 2011). ic tissues, including brain, kidney, liver, lung, skeletal muscle, These findings imply that the androgen is an essential factor placenta, salivary gland, spleen, thyroid, and thymus (Azumi for human PAP expression. Upstream deletion analysis con- et al., 1991; Hsing and Chokkalingam, 2006). TM-PAP was firmed that 577bp in -1356/-799 region is cis-acting enhancer also expressed in fibroblast, Schwann, and LNCaP cells, but region. Furthermore, prostate cancer specific PAP expres- not in PC-3 cells. This type I transmembrane (TM) protein had sion is increased due to NF-κB binding to AGGTGT motif in the extracellular NH2-terminal phosphatase activity and the −1254/−1249 region that is located in the PAP promoter region COOH-terminal lysosomal targeting signal (YxxF). TM-PAP (Zelivianski et al., 2004). Chloramphenicol acetyl transferase was localized in the plasma membrane-endosomal-lysosomal (CAT) reporter gene assay of the human PAP promoter re- pathway and found to colocalize with the lipid raft marker flo- vealed that the −1258 /−779 elements are essential for cell type-specific PAP expression (Zelivianksi et al., 2004). In addition, GAAATATGATA-like element necessary for transcription factor binding were found to exist in 6 sites in PAP regulatory regions (Shan et al., 2005). Based on electrophoretic mobility shift assay data, it was confirmed that −160/−130 and +239/+269 sites are related to tissue-specific PAP expression (Shan et al., 2003; Shan et al., 2005). Additionally, other sites should exist that regulate tissue-specific regulation of PAP in promoter regions.

DIFFERENT FORMS OF PAP

Although the level of PAP is increased in the circulation of patients with prostate cancer, its intracellular level and activity are greatly diminished in prostate cancer cells. This ap- parent discrepancy can be explained by the fact that there are two forms of PAP in prostate epithelial cells; the cellular form (cPAP) and secretory form (sPAP). The two forms of PAP differ in their biochemical properties such as hydrophobicity, isoelectric points and glycosylation patterns (Van Etten, 1982; Veeramani et al., 2005). sPAP is expressed only in the prostate (Solin et al., 1990) and is mostly released into seminal fluid (Ronnberg et al., 1981). The expression of cPAP becomes very high in normal prostate epithelial cells. But its level Fig. 3. Molecular inhibitory mechanism of cPAP to block prolifera- decreases in prostate cancer cells compared to neighboring tion and survival of prostate cells. When human ErbB-2 receptor normal cells (Reif et al., 1973; Lin et al., 2001). This decreased (HER-2) is activated by hyperphosphorylation, it transduces sig- expression of cPAP results in hyperphosphorylation of HER-2 naling for two pathways: RAF1/MAPK/ERK pathway and PI3K/ Akt/AR pathway. Blocking of these two pathways by prostatic acid at tyrosine residues and activation of downstream extracellu- phosphatase (PAP) can lead to inhibition of cell proliferation and lar signal-regulated kinase (ERK)/mitogen activated protein ki- survival. Functionally important residues for PAP activity together nase (MAPK) signaling, which can lead to androgen-indepen- with critical active sites (H12 & D258) are indicated. AR: androgen dent cell growth and prostate cancer development. Consistent receptor. http://dx.doi.org/10.4062/biomolther.2012.095 14 Kong and Byun. Varied Roles of Prostatic Acid Phosphatase

tillin-1 (Quintero et al., 2007). These findings emphasize the versy about its use for screening (Vihko et al., 2005; Shariat fact that the expression of PAP may not be exclusive to pros- et al., 2011). Indeed, there are still some significant controver- tatic tissue, and that this issue together with non-canonical sies over PSA screening because no study has successfully functions of PAP has to be taken into account for the success shown any significant correlation between such screening and of PAP-based immunotherapy without unwanted side effects a decline in mortality rate. (Madu and Lu, 2010). PSA also has (Antonarakis and Drake, 2010; Garcia, 2011; Gerritsen, 2012). limited predictive accuracy for predicting outcomes after treatment and for making clinical decisions about adjuvant and salvage therapies (Huang et al., 1993; Madu and Lu, 2010). CELL SIGNALING REGULATION BY PAP Hence, there has been an urgent need for novel biomarkers to supplement PSA for detection and management of prostate PAP can regulate prostate cell growth in two signaling path- cancer. Under these circumstances, there is now a renewed ways (Fig. 3). Human ErbB-2 (HER-2) can be homodimerized interest in PAP again because it has significantly higher corre- when it is phosphorylated at a tyrosine residue in early devel- lation with prostate cancer progression (Zimmermann, 2009). opmental stages of prostate cancer (Lin et al., 1994). Dimer- The cancer-specific survival (CSS) study, which tested 193 ized HER-2 then activates downstream ERK1/2 and MAPK, patients’ serum, showed that, when PAP concentration is <1.5 which in turn increases cell proliferation (Meng et al., 2000). U/L, 1.5-2.4 U/L and >2.5 U/L, the progression of prostate can- In another pathway, activated HER-2 stimulates PI3K signal- cer is 93%, 87% and 75% (p=0.013), respectively. However, ing. Upon activation, PI3K accumulates and activates Akt. Ac- when PSA concentration is <10 ng/ml, 10-20 ng/ml and > 20 tivated Akt then leads to phosphorylation and activation of AR ng/ml, the progression of prostate cancer is 92%, 76% and and phosphorylated AR stimulates cell proliferation (Vihko et 83% (p=0.393), respectively (Fang et al., 2008). These results al., 2005). PAP can act as a negative regulator of both path- strongly suggest that PAP may be a more suitable marker ways of HER-2 by dephosphorylation. By blocking Akt, PAP for prostate cancer and CSS than PSA. PAP appears to be can inhibit androgen-independent prostate cell growth. This particularly valuable in predicting distant failure in higher-risk is consistent with the observation that PAP expression has a patients for whom high levels of local control are achieved negative correlation with prostate cancer development (Saito with aggressive initial local treatment. As prostate cancer care et al., 2007). Indeed, late stage prostate cancer had a low lev- becomes increasingly focused on identifying the minority of el of PAP, suggesting a high risk for malignant tumor formation patients who would benefit from aggressive systemic therapy, (Merrick et al., 2005). In this regard, PAP can be regarded as a tumor suppressor mediating inhibition of cell growth (Veera- mani et al., 2005). Measuring levels of the active form of the protein EGFR in the tumor and its vicinity can provide a more reliable prognosis for individuals with prostate cancer. EGFR belongs to the same family as the prognosis marker HER-2 (Rubenstein et al., 2012), which is used today for breast cancer to determine the aggressiveness of a tumor that is to be treated with inhibitors of HER2 (Herceptin). In a similar way, it may be possible in the future to screen for the active form of EGFR to select patients with a poor prognosis and are suitable for treatment with inhibitors of EGFR. In order to use EGFR as a prognosis marker clinically in the future, further studies will need to target its expressions in other and larger material in prostate tumors.

PAP AS A USEFUL MARKER FOR PROSTATE CANCER

Despite the great progress in our understanding of the disease process and standardization of diagnostic criteria for prostate cancer, the majority of prostate tumors are detected at early stages with uncertain prognosis (Larne et al., 2012). Previous studies have shown that PAP can serve as a prostate cancer marker by proportionally increasing secretory PAP expression as prostate cancer progresses (Azumi et al., 1991; Wang et al., 2005; Gunia et al., 2009). High levels of PAP expression were detected in high Gleason score prostate Fig. 4. Schematic diagram of Provenge trial. The stages of Sip- cancers as determined by immunohistochemistry (Gunia et uleucel-T treatment for patients with prostate cancer are shown. al., 2009). However, the introduction and widespread adoption Sipuleucel-T treatment is similar to a dendritic cell (DC) vaccine. It of PSA has largely displaced PAP in the diagnosis and treat- is a United States Food and Drug Administration (FDA)-approved autologous cell-based immunotherapy that targets prostatic acid ment of prostate cancer. This was because PSA was more phosphatase (PAP) as a treatment for advanced prostate can- sensitive than PAP in the detection of prostate cancer in the cer. Modified from Garcia (2011) and Gerritsen (2012). GM-CSF: serum. However, the use of PSA has also led to over-diagno- granulocyte-macrophage colony-stimulating factor; APC: antigen- sis and overtreatment of prostate cancer resulting in contro- presenting cells.

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a reevaluation of the potential contribution of the PAP test cinoma Treatment) trial of 512 patients with asymptomatic or seems timely (Taira et al., 2007). Investigation of any poten- minimally symptomatic metastatic CRPC, which served as the tial interplay between PAP and PSA and between PAP and basis for the licensing approval of sipuleucel-T, vaccine treat- other markers are also warranted. Recently, diagnostic utility ment resulted in a 4.1 month improvement in median over- of P504S/p63 cocktail in verifying prostatic carcinoma involve- all survival compared with placebo (25.8 months versus 21.7 ment in seminal vesicles were evaluated (Harvey et al., 2010). months, respectively) with a 22% relative reduction in the risk The use of the single-color P504S/p63 immunohistochemi- of death [hazard ratio (HR): 0.78, p=0.03] (Gerritsen, 2012). cal stain cocktail was recommended for identifying prostatic The delayed onset of response reflected in the late separation carcinoma involving the seminal vesicle and for distinguishing of survival curves has been reported in many clinical trials of benign prostatic glands from prostatic carcinoma when there immunotherapeutic agents and is known to impact on clinical is a question of seminal vesicle invasion. It was argued that dynamics, highlighting the need for suitable end points to as- P504S/p63 cocktail is superior to PSA or PAP when sections sess efficacy (Gerritsen, 2012). On the other hand, the PAP contain both seminal vesicle and benign glands because PSA encoded DNA vaccine is currently undergoing clinical trials and PAP cannot distinguish benign from malignant glands that aim to prevent and treat prostate cancer. Ten of twenty- (Harvey et al., 2010). two patients showed antigen-specific T cell proliferation and upregulation of CD8+INFg (McNeel et al., 2009, Lubaroff, 2012). DNA vaccines encoding PAP are expected to be an PAP AS A USEFUL ANTIGEN FOR PROSTATE CANCER effective way to prevent and treat prostate cancer. To date, a THERAPY lot of prostate cancer-associated antigens such as PSA, PAP, or PSMA have been cloned and are being tested as a com- Based on the good prognostic value of PAP and the po- ponent of investigational therapeutic cancer vaccines (Vieweg tential usefulness of PAP as an antigen, an immunotherapy and Dannull, 2005). But because prostate cancer is known to employing autologous PAP-loaded dendritic cells was ini- be a heterogeneous disease with a number of different genetic tiated (Drake, 2010). This FDA-approved therapy termed make-ups, personalized therapeutic strategies guided by the PROVENGE (Sipuleucel-T) works on the basic idea that over use of novel molecular imaging will be necessary to success- 95% of prostate cancer cells express PAP (Drake, 2012). fully test the utility of such targeted agents in patients whose Treatment with sipuleucel-T comprises a number of stages tumors will depend upon that antigen target for tumor growth (Fig. 4). First, autologous peripheral blood mononuclear and/or survival. cells (PBMCs) including antigen-presenting cells (APCs) are pulsed ex vivo and activated in vitro with a recombinant fusion protein (PA2024) that couples the vaccine target (PAP) to INVERSE CORRELATION BETWEEN PAP AND OLIGO- granulocyte-macrophage colony-stimulating factor (GM-CSF) SPERMIA (Garcia, 2011; Gerritsen, 2012). This PAP and GM-CSF fusion protein is presented to antigen presenting cells (APCs) that PAP has an essential role not only in prostate cancer but are collected from the patient. These activated APCs are then also in many other physiological functions (Fig. 5). PAP is introduced to the patient for induction of T cells in vivo. Activat- also expressed in normal prostate tissue, which is an indica- ed T cells now attack prostate cancer cells in the patient, thus tion that PAP has a prostate-specific physiological role. PAP treating the cancer (Cheever and Higano., 2011; Sims, 2012). is abundant in seminal fluid and is therefore thought to be an In the phase III IMPACT (Immunotherapy Prostate AdenoCar- important factor in fertilization, helping to increase the mobility

Fig. 5. Diverse roles of PAP including non-canonical functions. Traditionally, PAP was a molecule mainly involved in prostate cancer diagnosis and treatment. Recently, however, inherent phosphatase activity of PAP broadens its role in other areas such as oligospermia, SEVI, and pain suppression. http://dx.doi.org/10.4062/biomolther.2012.095 16 Kong and Byun. Varied Roles of Prostatic Acid Phosphatase

of sperm (Afzal et al., 2003). On the other hand, a previous SEVI fibrillization under physiological conditions (Shefticet al., study of 365 semen samples has shown that PAP concentra- 2012). tion is inversely associated with sperm concentration (Dave and Rindani, 1988; Singh et al., 1996). Moreover, other group showed that the highest phosphatase activity was detected SUMMARY AND CONCLUSIONS in azoospermic men and, when phosphatase activity was decreased, the concentration of sperm tended to recover to nor- Prostate cancer research in the past decade has made mal concentration (Dave and Rindani, 1988; Collins and Ben- huge stride in the understanding of the disease process and nett, 2011). Although molecular mechanisms are still unclear standardization of diagnostic criteria. Although great progress as to how PAP induces oligospermia, PAP can be used as an has been made, there still remain many areas of uncertainty effective marker for oligospermia (Coussens and Werb, 2002). and debate. The revolution towards a synthesis of diagnosis and therapy together with sound prognostic models is only just beginning. One of the major hurdles in prostate cancer ther- ANTINOCICEPTIVE EFFECT OF PAP apy is that more than 70% of patients fall into a group where very little can be said about their prognosis with today's mark- While PAP was classically considered to be a non-specific ers. This in turn means that certain patients are over-treated phosphomonoesterase (E.C. 3.1.3.2) (Ostrowski and Kuciel, with therapies that can lead to serious side effects and that 1994), sPAP and transmembrane PAP could function as ecto- other patients who really need intensive treatment do not get nucleotidases that hydrolyzes extracellular adenosine 5′-mo- it or get it too late. Therefore, a panel of sound biomarkers will nophosphate (AMP) to adenosine and Pi. This extracellular be needed to achieve sufficient degree of certainty in guiding adenosine leads to a decrease in chronic pain by activating clinical decisions. PAP has a significantly higher correlation A1R in nociceptive neurons (Zylka et al., 2008). sPAP is glyco- with the morphological characteristics of prostate cancer and sylated at three asparagine residues (N62, N188, N301) and can provide a more efficient prognosis than any other markers has potent antinociceptive effects when administered to mice currently available. Since PAP is a proportional measure of (Hurt et al., 2012a). Secretion and post-translational carbohy- prostate cancer progression, it can also be used in immuno- drate modifications were found to be required for PAP protein therapy of prostate cancer. However, utility of PSA and other stability and catalytic activity. Also, it was found that deletion of potential markers must also be considered to ensure best PAP reduces extracellular AMP hydrolysis in nociceptive neu- diagnosis and prognosis of prostate cancer. More molecu- rons and in the dorsal spinal cord (Street et al., 2011). Intrathe- lar studies on PAP increase in prostate cancer and different cal injection of sPAP had three day long antinociceptive effects forms of PAP including transmembrane PAP are needed to in mouse models of inflammatory pain and neuropathic pain unveil the detailed mechanism of PAP in prostate cancer. Al- (Sowa et al., 2009). In addition, sPAP had enduring (>7 days) though PAP has been used as a marker of prostate cancer A1R-dependent antinociceptive effects if injected intrathecally for decades, normal physiological functions of PAP must still before nerve injury or inflammation (Sowaet al., 2010). These be identified. Recent characterization of PAP’s involvement in findings altogether suggest that a recombinant version of hu- pain suppression, oligospermia, and viral infection is shedding man sPAP could be used as a treatment for chronic pain or for newer lights on the role played by PAP. To better understand preemptive analgesia (Hurt et al., 2012b). the diverse roles of PAP in vivo, a systematic and integrated approach will be needed. SEMEN-DERIVED ENHANCER OF VIRUS INFECTION (SEVI) ACKNOWLEDGMENTS

PAP may play an important role in the transmission of HIV. The present research was conducted by the research fund By screening a complex peptide/protein library derived from of Dankook University in 2010. human semen, German group could show that naturally oc- curring fragments of the abundant semen marker prostatic acidic phosphatase (PAP) form amyloid fibrils (Münch et al., REFERENCES 2007). These fibrils, termed Semen-derived Enhancer of Virus Infection (SEVI), capture HIV virions and promote their attach- Abrahamsson, P. A., Lilja, H., Falkmer, S. and Wadström, L. B. (1988) ment to target cells, thereby enhancing the infectious virus Immunohistochemical distribution of the three predominant secretory proteins in the parenchyma of hyperplastic and neoplastic titer by several orders of magnitude. Physiological concentra- prostate glands. Prostate 12, 39-46. tions of SEVI amplified HIV infection of T cells, macrophages, Afzal, S., Ahmad, M., Mushtaq, S., Mubarik, A., Qureshi, A. H. and ex vivo human tonsillar tissues, and transgenic rats in vivo, as Khan, S. A. (2003) Morphological features correlation with serum well as trans-HIV infection of T cells by dendritic or epithelial tumor markers in prostatic carcinoma. J. Coll. Physicians. Surg. cells. Since amyloidogenic PAP fragments are abundant in Pak. 13, 511-514. seminal fluid and boost semen-mediated enhancement of HIV Antonarakis, E. S. and Drake, C. G., (2010) Current status of immuno- logical therapies for prostate cancer. Curr. Opin. Urol. , 241-246. infection, PAP may be a future target to combat the spread 20 Azumi, N., Traweek, S. T. and Battifora, H. (1991) Prostatic acid phos- of HIV infection. In another instance, SEVI greatly increased phatase in carcinoid tumors: Immunohistochemical and immunob- xenotropic murine leukemia virus-related virus (XMRV) infec- lot studies. Am. J. Surg. Pathol. 15, 758-790. tions of primary prostatic epithelial and stromal cells (Hong et Batta, A., Panag, KMDS. and Singh, J. (2012) Diagnosis of prostate al., 2009). Recently, it was shown that Cu(II) and Zn(II) inhibit cancer --- Role of biomarkers. Int. J. Cur. Biomed. Phar. Res. 2, fibrillization of SEVI, suggesting that the metals may modulate 339-345.

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